A considerably high mortality rate in Japan is caused by ischemic diseases due to vascular occlusion, such as myocardial infarction and cerebral infarction. There are also another ischemic diseases which are not fatal but deteriorate QOL (quality of life), such as aortic obstructive diseases for which amputation of lower extremity is forced. To overcome these ischemic diseases, angiogenesis therapy by which sufficient circulation is supplied through newly generated blood vessels is hoped very much. Angiogenesis plays an important role not only in the treatments of ischemic diseases, but also in the adaptation of biomaterials. Some artificial biomaterials including apatite and titanium have been used for filling bone defect or implant. These artificial biomaterials have poor compatibilities with the surrounding soft and hard tissues, so that they often cannot exhibit their primary function well.
To improve the compatibility with the surrounding soft and hard tissues, it has been proposed to use peptide derivatives having bio-adhesive functions. For example, it has been proposed to use a composite as an artificial bone, which is a mixture of apatite carbonate having the composition and crystallinity similar to those of hard tissue in the body, and collagen which is one of the bio-adhesive functions (K. Nokihara et al., The Japanese Peptide Society, Osaka, 373–376, 2001., Development of Biomimetic Materials: Novel Composite Material Carrying Immobilized Functional Peptides; M. Okazaki et al., Dentistry in Japan, 37, 95–100, 2001, A New Concept of CO3 apatite-Collagen Composites with Adhesion Motif as Biomaterials). This composite has a good biocompatibility and is a promising biomimetic artificial bone.
If blood vessels are newly formed on the surfaces and insides of such biomaterials, nutrients and oxygen are sufficiently supplied to the cells on the surfaces and insides of the transplanted biomaterials by means of abundant blood at an early stage after surgery, so that optimum environment for the cells to function is formed, thereby advantageously attaining good taking of the materials to the body.
On the other hand, peptides which have great advantages in the safeties in view of side effects, metabolic properties and the like, are easy to design, and highly efficient synthesis methods and characterization methods have been established. In addition, amino acid derivatives are convenient building units for the construction of combinatorial chemical libraries, and optimization thereof can be attained by solid phase synthesis methods in a short time. Thus, it is advantageous that peptides having a relatively low molecular weight and exhibiting angiogenic activities, which may improve interactions between biomaterials and the surrounding soft and hard tissues, may be synthesized and administrated alone or conjugates, that is, such peptides are immobilized onto biomaterials. However, low molecular peptides or peptide-mimetic organic compounds having prominent angiogenic activities are scarcely known.